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Evidence for the Importance of 5'-Deoxy-5-fluorouridine Catabolism in Humans from ¹⁹F Nuclear Magnetic Resonance Spectrometry¹

Laboratoire des IMRCP, UA CNRS 470 [M. C. M-M., A. L., R. M.], and Service de RMN Haut Champ [J-P. B, M. B.], Université Paul Sabatier, 31062 Toulouse Cédex and Centre Claudius Regaud, 31000 Toulouse [J-P. A., J. B.], France

The use of a new methodology, ¹⁹F nuclear magnetic resonance, has allowed detection of all the fluorinated metabolites in the biofluids of patients treated with 5'-deoxy-5-fluorouridine (5'-dFUrd) injected i.v. at a dose of 10 g/m² over 6 h. This technique, which requires no labeled drug, allows a direct study of the biological sample with no need for extraction or derivatization and a simultaneous identification and quantitation of all the different fluorinated metabolites. As well as the already known metabolites, unmetabolized 5'-dFUrd, 5-fluorouracil, and 5,6-dihydro-5-fluorouracil, the presence of -fluoro-ß-ureidopropionic acid, -fluoro-ß-alanine (FBAL), N-carboxy--fluoro-ß-alanine, and the fluoride anion F^- is reported. The catabolic pathway proposed for 5'-dFUrd is analogous to that of 5-fluorouracil, completed with FBALF^- step, and the plasmatic equilibrium of FBAL with N-carboxy--fluoro-ß-alanine, its N-carboxy derivative. The quantitative analysis of the different metabolites found in plasma and urine emphasizes the significance of the catabolic pathway. High concentrations of -fluoro-ß-ureidopropionic acid and FBAL are recovered in plasma from 3 h after the beginning of the perfusion to 1 h after its end. The global urinary excretion results show that there is a high excretion of 5'-dFUrd and metabolites. Unchanged 5'-dFUrd and FBAL are by far the major excretory products and are at nearly equal rates. The protocol followed in this study produces relatively low but persistent plasmatic concentrations of 5-fluorouracil throughout the perfusion.

¹ Presented in part at the 76th Annual Meeting of the American Association for Cancer Research, Houston, Texas, May 22 to 25, 1985 (1). This study was supported by grants from Université Paul Sabatier and the Clinical Screening Group of the European Organization for Research and Treatment of Cancer (EORTC).

² Present address: Institut Gustave Roussy, Unité de la Grange, 77176 Savigny-Le-Temple, France.

³ To whom requests for reprints should be addressed, at Laboratoire des IMRCP, Université Paul Sabatier, 118, route de Narbonne, 31062 Toulouse Cédex, France.

Received 7/ 9/85. Revised 12/12/85. Accepted 12/20/85.